In dopaminergic neurons, a-synuclein (aS) partitions between a disordered cytosolic state and a lipid-bound state. Binding of aS to membrane phospholipids is implicated in its functional role of synaptic regulation, but also impacts fibril formation associated with Parkinson's disease. Three familial variants of the presynaptic protein a-synuclein (aS),1 A30P, E46K, and A53T, correlate with rare inherited Parkinsons disease (PD), while wild-type aS is implicated in sporadic PD. The classic manifestation of both familiar and sporadic PD is the formation of fibrillar structures of aS which accumulate as the main component in intraneuronal Lewy bodies. At presynaptic termini, the partitioning of aS between disordered cytosolic and membrane-bound states likely mediates its proposed role in regulation of reserve pools of synaptic vesicles. Previously we reported on multiple distinct phospholipid-binding modes of aS with slow binding kinetics. We have studied the phospholipid-binding properties of the disease variants, viewed by solution NMR in a residue-specific manner. Our results agree qualitatively with previous biophysical studies citing overall decreased lipid affinity for the A30P mutation, comparable affinity for A53T, and increased binding of E46K, relative to wild-type aS. Additionally, our NMR results describe the distribution of lipid-bound states for aS: the population of the SL1 binding mode (residues 3-25 bound as a helix) is augmented by each of the disease variants, relative to wild-type aS. We propose that the SL1 binding mode, which anchors the N-terminus of aS in the lipoprotein complex while the hydrophobic NAC region remains dynamically disordered, is prone to intermolecular interactions which progress towards disease-associated oligomers and fibrils. The elevation of the SL1 binding mode, unchecked by a proportionate population of binding modes incorporating the full N-terminal domain, may well account for the increased toxicity of the A30P, E46K, and A53T disease variants of aS.